Dopamine reuptake blockers

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Froimowitz, Mark, Kuo-Ming Wu, William Paredes, Anthony Giordano, Jordan Spector, Xinhe Liu, Marino Lepore, and Eliot L Gardner. 1997. "Effects of a Slow-Onset, Long-Acting Dopamine Reuptake Blocker on Cocaine Self-Administration and on Nucleus Accumbens Dopamine." Society for Neuroscience Abstracts 23 1110. 

Froimowitz, Mark, Kuo-Ming Wu, and Roger D. Spealman. 1996, "Slow Onset, Long-Lasting Dopamine Reuptake Blockers as Potential Medications for the Treatment of Cocaine Abuse." Society for Neuroscience Abstracts 22 703. 

The title compound, l-[bis-(4-fluorophenyl)methyl]-4-(3-phenylpropenyl) piperazine, 123, clinically used as a calcium channel blocker of the piperazine class166, has been labelled with 18F by alkylation of Af-cinnamylpiperazine with 4-[18F]fluoro-4 -fluoroben-zhydryl chloride 124 (equation 73)167. The biodistribution of 123, its effect on the dopamine reuptake blockers and metabolic products are under investigation167. 

Bupropion dopamine reuptake blocker used in smoking cessation... 

Additional dqpamine releasers will probably be tested since this mode of action has been identified. Effective and selective dopamine reuptake blockers should be explored as another therapeutic approach. Direct dopamine receptor stimulation is probably the most active present area. In view of the complex catecholamine physiology other neurological target uses for these leads will be sovight and undoubtedly found. Combinations of the last 3 approaches will be primarily initiated by clinicians. ... 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

Serotonin and dopamine reuptake inhibition. Dual reuptake blockers of both serotonin and dopamine are in clinical testing. Although the SSRI sertraline has some dopamine reuptake inhibition as well as more potent serotonin reuptake inhibition, minaprine and bazinaprine have more potent dopamine actions and are thus dual sero-tonin/dopamine agents. 

DA = dopamine reuptake inhibitor NE = norepinephrine hibitor alpha-2 = alpha-2-adrehergic receptor blocker. 

First, the extracts of the roots of Ruscus aculeatus at higher concentrations caused their contractions of canine cutaneous veins in part because the extracts could reveal an indirect sympathomimetic effect for the inhibition to the neuronal uptake such as cocaine (40) (Figure 11) of a serotonin-norepinephrine-dopamine reuptake inhibitor [31]. Here, a selective ai-adrenergic blocker prazosin (41) and a selective a2-adrenergic blocker rauwolscine (a-yohimbine. 42) (Figure 11) are present in the canine saphenous vein [32, 33] might greatly contribute to their contractile response to the extracts of the roots of Ruscus aculeatus. 

Conformational Search Medium-sized Molecules Dopamine Agonists, Antagonists, and Reuptake Blockers Drug... 

The potent dopamine reuptake inhibitor (-l-)-indatraline 7 was prepared in a few steps after the reaction of methyl (3,4-dichlorophenyl)diazoacetate 9 with an excess of 1,4-cyclohexadiene, which was used as a synthetic equivalent of a phenyl group, in the presence of a catalytic amount of Rh2(5 -DOSP)4. The product 11 was isolated in a good yield and a high enantiomeric excess. Finally, 7 was obtained in 99% ee after recrystallization. The synthesis of (+)-cetiedil 8, an effective K channel blocker, was carried out in a similar approach. The enantioselective C—H insertion of... 

Cocaine is a tropane-type derivative with several chiral centres and only the (lJ ,2f ,3S,5S)-stereoisomer, also called (—)-cocaine, appears to have appreciable psychostimulant properties. Its primary mode of action is based on blockage of the dopamine transporter which is defined as a directly mediated mechanism. Cocaine is therefore classified as a dopamine blocker rather than dopamine releaser, as is the case with some amfetamines. A large number of 2P,3P-cocaine analogues are well tolerated by the dopamine transporter but not necessarily by the noradrenaline or serotonin counterparts. This means that dopamine reuptake blockage alone is not necessarily sufficient to reinforce consumption, and appropriate stmctural modifications could lead to the development of treatment options for cocaine abuse. 

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

The antidepressants, generally, produce their therapeutic effects by blocking the reuptake of one or more catecholamines (norepinephrine, serotonin, and dopamine), which leads to a decrease (down-regulation) of the number of post-synaptic receptors—generally within seven to twenty-one days, coinciding with the onset of clinical effect (see chapter 3). The MAOIs block monoamine oxidase, which metabolizes the catecholamines stored at the nerve ending of the presynaptic neuron—thereby making more catecholamine available. Stimulants increase the release of catecholamines. Buspirone is a 5-HT lA receptor blocker. 

Amphetamine. Amphetamine facilitates dopamine release and inhibits norepinephrine reuptake, which results in increased postsynaptic norepinephrine levels. Amphetamine increases wakefulness and reduces REM sleep. These effects may be prevented by the preadministration of pimozide, a specific D, receptor antagonist, which inhibits presynaptic dopamine release. Propranolol, a p-adrenergic blocker, does not prevent the effect of amphet-... 

It is a central nervous system stimulant, preventing reuptake of neurotransmitters like dopamine (see pl69), serotonin (p451), and noradrenaline (p9). This impacts on the pleasure center of the brain, explaining its stimulant effects. It is also a sodium-channel blocker, which causes its anesthetic effects, because it interferes with the transmission of nerve impulses. 

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